Immunotherapy to prevent drug-resistant tuberculosis

项目摘要/摘要 结核分枝杆菌(Mtb)对目前一线抗菌药物的耐药性严重且呈上升趋势。 对公共健康构成威胁，每年导致近500,000例新结核病病例和170,000人死亡。 对药物敏感疾病的治疗是漫长而复杂的，患者的不依从性会加剧 出现耐药(DR)结核病病例，治疗时间更长、毒性更大、成本更高、 治愈率也更低。 目前的提案旨在利用现有的二线开发一种创新的联合疗法 药物卷曲霉素，一种新的高级杀菌抗生素，舒替唑胺，以及候选治疗药物 疫苗作为一种吸入性产品提供，为改善DR-TB的治疗提供了巨大的潜力。一个 有效的治疗方法，既针对病原体，又能增强宿主的免疫反应，以加速 清除细菌，防止复发，缩短治疗，将在戏剧性地 减少结核分枝杆菌病原体的影响。我们将利用专有疫苗佐剂的力量，以及 临床阶段疫苗抗原ID93，已进入第二阶段人类临床测试。此应用程序是一个 推广我们控制结核病的系统和方法。在过去的二十年里，我们 已经将这一战略应用于开发可行的候选疫苗，如M72/AS01E和ID93/GLA- SE(均为临床分期检测)。目前，据我们所知，ID93/GLA-SE是唯一的候选结核病疫苗 正在进行中，已经测试了对耐药结核病的有效性，以及#年的预防和治疗 多种结核病动物模型。资助这一R01项目以开发一种候选治疗性疫苗 用药物辅助治疗耐药结核病将解决这一全球传染病威胁。

Project Summary / Abstract Mycobacterium tuberculosis (Mtb) resistant to current first-line antibacterial agents is a serious and growing public health threat, causing nearly 500,000 new tuberculosis (TB) cases and 170,000 deaths annually. Treatments for drug-sensitive disease are lengthy, complex, and patient noncompliance exacerbates the development of drug-resistant (DR) TB cases, for which treatments are even more prolonged, toxic, expensive, and have lower cure rates. The current proposal is designed to develop an innovative combination regimen using an existing second line drug, Capreomycin, a new class of superior bactericidal antibiotic, Sutezolid, and a candidate therapeutic vaccine delivered as an inhaled product that offers significant potential to improve treatment of DR-TB. An effective treatment that targets both the pathogen and boosts the host immune response to accelerate bacterial clearance, prevent relapse, and shorten therapy, would play an important role in dramatically reducing the impact of the Mtb pathogen. We will leverage the strength of proprietary vaccine adjuvants, and a clinical stage vaccine antigen, ID93, that has entered Phase 2 human clinical testing. This application is an extension of our systematic and methodical approach towards controlling TB. Over the last twenty years, we have applied this strategy towards developing viable vaccine candidates such as M72/AS01E and ID93/GLA- SE (both in clinical stage testing). At present, to our knowledge, ID93/GLA-SE is the sole TB vaccine candidate in the pipeline that has been tested for efficacy against DR-TB, as well as for prophylaxis and therapy in multiple animal models of TB. Funding this R01 project to develop a candidate therapeutic vaccine used as adjunctive treatment with drugs for DR-TB will address this global infectious disease threat.